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TOPIC HIGHLIGHT
Daniel C Baumgart, MD, PhD, Series Editor
Cancer in inflammatory bowel disease
Jianlin Xie, Steven H Itzkowitz
Jianlin Xie, Steven H Itzkowitz, Division of Gastroenterology,
Department of Medicine, Mount Sinai School of Medicine, New
York City, NY 10029, United States
Correspondence to: Steven H Itzkowitz, MD, GI Division, Box
1069, Mount Sinai School of Medicine, One Gustave Levy Place,
New York City, NY 10029,
United States. steven.itzkowitz@msnyuhealth.org
Telephone: +1-212-6599697 Fax: +1-212-8492574
Received: May 16, 2007 Revised: June 11, 2007
Abstract
Patients with long-standing inflammatory bowel disease
(IBD) have an increased risk of developing colorectal cancer
(CRC). Many of the molecular alterations responsible
for sporadic colorectal cancer, namely chromosomal
instability, microsatellite instability, and hypermethylation,
also play a role in colitis-associated colon carcinogenesis.
Colon cancer risk in inflammatory bowel disease increases
with longer duration of colitis, greater anatomic extent
of colitis, the presence of primary sclerosing cholangitis,
family history of CRC and degree of inflammation of
the bowel. Chemoprevention includes aminosalicylates,
ursodeoxycholic acid, and possibly folic acid and statins.
To reduce CRC mortality in IBD, colonoscopic surveillance
with random biopsies remains the major way to detect
early mucosal dysplasia. When dysplasia is confirmed,
proctocolectomy is considered for these patients. Patients
with small intestinal Crohns disease are at increased
risk of small bowel adenocarcinoma. Ulcerative colitis
patients with total proctocolectomy and ileal pouch anal-
anastomosis have a rather low risk of dysplasia in the ileal
pouch, but the anal transition zone should be monitored
periodically. Other extra intestinal cancers, such as
hepatobiliary and hematopoietic cancer, have shown
variable incidence rates. New endoscopic and molecular
screening approaches may further refine our current
surveillance guidelines and our understanding of the
natural history of dysplasia.
2008 WJG . All rights reserved.
Key words: Colon cancer; Inflammatory bowel disease;
Dysplasia; Chemoprevention; Colonoscopy; Genomic
instability
Xie J, Itzkowitz SH. Cancer in inflammatory bowel disease. World
J Gastroenterol 2008; 14(3): 378-389 Available from: URL:
http://www.wjgnet.com/1007-9327/14/378.asp DOI: http://dx.doi.
org/10.3748/wjg.14.378
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World Journal of Gastroenterology ISSN 1007-9327
2008 WJG. All rights reserved.
INTRODUCTION
The two forms of inflammatory bowel disease (IBD),
Crohns disease (CD) and ulcerative colitis (UC), are
characterized by chronic, relapsing inflammation of
the intestines. First described in a report by Crohn and
Rosenberg in 1925[1], colorectal cancer (CRC) in patients
with IBD has long been recognized. Even years after
their disease is controlled with medications, IBD patients
still live with the fear of developing cancer. CRC is the
most common site of cancer in IBD, although cancer
in other organs can occur. Together with the hereditary
syndromes of familial adenomatous polyposis and
hereditary nonpolyposis colorectal cancer, IBD is among
the top three high-risk conditions for CRC. To date, our
understanding of CRC pathobiology has come from
studies of patients with UC more so than Crohns colitis.
This review will focus mainly on the problem of CRC,
and then address other cancers such as small intestinal
adenocarcinoma, cholangiocarcinoma, and hematologic
malignancies.
COLORECTAL CANCER in Patients with
IBD
Prevalence and Incidence of CRC
The exact magnitude of the risk of cancer has been difficult
to quantify due to various biases and methodological errors
in published studies. Early estimates of CRC complicating
UC were based on crude percentages and all were from
major medical institutions, predominantly tertiary referral
centers. Studies from these centers often included a greater
proportion of patients who had more severe disease and
cancer had already complicated their colitis. These center-
based studies often overestimate the risk. Later population-
based studies tended to include more patients with limited
disease or those who have undergone colectomy and may
thereby underestimate the true risk. Based on a 2001 meta-
analysis by Eaden et al, including 116 studies from around
the world, the prevalence of CRC in patients with UC
is approximately 3.7% overall and 5.4% for those with
pancolitis[2]. In comparison, CRC in Crohns disease has
been less well studied. Early studies showed no statistically
significant increase in cancer risk among the Crohns
disease patients. However, the lack of the risk of cancer in
these studies was often due to inclusion of all patients with
Crohns disease and failed to correct for the small subsets
of those with extensive, longstanding and unresected
colonic disease. Hence, when patients with longstanding,
 Xie J et al. Cancer in IBD
Sporadic colon cancer
Aneuploidy
MSI
methylation
k-ras
APC Sialyl-Tn COX-2 c-src
Normal Early Intermediate
mucosa adenoma adenoma
Colitis-associated colon cancer
Aneuploidy
methylation
MSI
p53 sialyl-Tn p53
mut COX-2 LOH DCC c-src
Negative Indefinite Low-grade
dysplasia dysplasia dysplasia
anatomically substantial Crohns colitis are considered, the
risk of CRC is similar between Crohns colitis and UC[3].
Indeed, a population-based study from Manitoba, Canada
found that the risk for colon cancer among patients with
both UC and Crohns colitis is approximately 2-3 fold
greater than the general population and that the risk of
rectal cancer is increased 2-fold in UC but not Crohns
colitis[4].
Clinical features of colitis-associated CRC
Compared with sporadic colorectal carcinoma (SCC), CRC
arising in patients with IBD has several distinguishing
clinical features. Colitis-associated colorectal cancer (CAC)
affects individuals at a younger age than the general
population. CAC progresses to invasive adenocarcinoma
from flat and nonpolypoid dysplasia more frequently
than SCC. CACs more often have a higher proportion
of mucinous and signet ring cell histology. There is
background of chronic inflammation in colitis and a
higher rate of two or more synchronous primary CRCs.
The multifocality of CAC relates to the broader field effect
of mucosal inflammation that gives rise to the neoplasia.
In some studies, patients were found to have cancer more
proximal in the colon. Finally, the sequence of molecular
events leading from dysplasia to invasive adenocarcinoma
is different from that of SCC (discussed below).
Molecular features of sporadic colon cancer
To place the molecular pathogenesis of colitis-associated
neoplasia in proper perspective, it is important to appreciate
the molecular events involved in the development of SCC.
SCC arises as a result of genomic instability. The two
main types of genomic instability that contribute to colon
carcinogenesis are chromosomal instability (CIN) and
microsatellite instability (MSI), accounting for 85% and 15%
of SCC, respectively. Chromosomal instability results in
abnormal segregation of chromosomes and abnormal DNA
content (aneuploidy). As a result, loss of chromosomal
material (loss of heterozygosity) often occurs, such as APC
and p53. These genes can also be rendered nonfunctional by
mutation.
Loss of APC function is typically an early event in SCC
379
Figure 1 Comparison of molecular
alterations in sporadic colon cancer and
colitis-associated colon cancer. Mut,
DCC/DPC4 p53 mutation. Modified from Ref 71. With
permission.
Late
Carcinoma
adenoma
k-ras APC
High-grade
Carcinoma
dysplasia
pathogenesis. The APC gene thus has been considered
the gatekeeper of the colon (Figure 1). Some 85% of
all sporadic and inherited colorectal tumors show loss of
APC function, usually through protein truncation or allelic
loss[5]. The APC gene is located on chromosome 5q21-q22.
The key tumor suppressor function of the APC protein
lies in its ability to destabilize free -catenin[6]. Among the
15% of colon carcinomas that retain wild-type APC, point
mutations have been found in -catenin that change one
of the four serine/threonine residues in the N-terminus,
the putative targets of glycogen synthase kinase-3 (GSK-
3)[7]. These mutations thus render -catenin refractory
to phosphorylation by GSK-3, increasing free -catenin
levels. Accumulation of stabilized free -catenin is an
early event and perhaps the initiating event in intestinal
tumorigenesis. Inactivation of both APC alleles is found
in a majority of small colorectal adenomas in humans and
in the smallest detectable tumors in mice heterozygous for
an inactivating mutation in APC[8]. Furthermore, intestine-
specific expression of a dominant-negative form of
-catenin, which lacks the putative GSK-3 targets sites,
leads to the development of adenomas[9]. How the loss of
APC or stabilization of -catenin leads to development
of cancer is not yet fully understood. Once a sporadic
adenoma forms, other changes in genetic regulation occur,
such as induction of k-ras oncogene and loss of function
of tumor suppressor genes on chromosome 18q in the
region of the deletion in colon cancer (DCC) and in
pancreatic cancer (DPC4) genes. Loss of p53 gene function
occurs late and is believed to be the defining event that
drives the adenoma to carcinoma.
Tumors that arise via the CIN/tumor suppressor
gene pathway are typically microsatellite stable (MSS).
The remaining 15% of sporadic CRCs arise through the
MSI pathway. The MSI pathway involves the primary loss
of function of genes that usually repair DNA base-pair
mismatches that occur during the normal process of DNA
replication in dividing cells. In humans, at least six different
proteins (hMS H2, hMLH1, hPMS1, hPMS2, hMS H6,
and hMLH3) comprise the mismatch repair system [10].
These proteins form specific heterodimers to coordinate
DNA repair and the recruitment of other proteins, such
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 380 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol
as polymerases and helicases, necessary for mismatch
repair. Germline mutations of DNA mismatch repair
genes, predominantly hMLH1 (33%) and hMSH2 (31%),
are responsible for the familial syndrome of heriditary
nonpolyposis colon cancer[11]. In addition, approximately
15% of sporadic tumors from the colon, rectum, and
other organs demonstrate MSI[12]. Interestingly, the most
common mechanism causing MSI in sporadic colon
cancers is not genetic mutation, but rather transcriptional
silencing of hMLH1 as a consequence of methylation of
the hMLH1 promoter[13].
Epigenetic alterations can also contribute to altered
gene expression in colon carcinogenesis. The CpG
island methylator phenotype occurs when cytosines
in the promoter region of genes become extensively
methylated. A number of human cancer genes that
contain hypermethylation of promoter CpG islands have
been identified [14]. These include hMLH, p16 INK4a, and
E-cadherin. The process of methylation is an area of intense
investigation, and it is anticipated that this line of research
should help to define further the molecular pathways
involved in CRC in a variety of clinical settings.
Molecular features of CRC in IBD
The neoplastic transformation in IBD is thought to be
similar to the adenoma-carcinoma sequence in sporadic
CRC (Figure 1). However, unlike SCC, where dysplastic
lesions arise in one or two focal areas of the colon, in
colitic mucosa, it is not unusual for dysplasia or cancer to
be multifocal, reflecting a broader field effect. Many of
the molecular alterations responsible for sporadic CRC
development also play a role in colitis-associated colon
carcinogenesis. The emerging evidence suggests that
the two major pathways of CIN and MSI also apply to
CACs and with roughly the same frequency (85% CIN,
15% MSI). Distinguishing features of CAC, however, are
differences in the timing and frequency of these alterations
(Figure 1). For example, APC loss of function, considered
to be a very common early event in SCC, is much less
frequent and usually occurs late in the colitis-associated
dysplasia-carcinoma sequence. Conversely, p53 mutations
in sporadic neoplasia usually occur late in the adenoma-
carcinoma sequence, whereas in patients with colitis, p53
mutations occur early and are often detected in mucosa
that is non-dysplastic or indefinite for dysplasia.
Methylation is assuming increasing importance as
a mechanism contributing to the genetic alterations in
CAC (Figure 1). Methylation of CpG islands in several
genes seems to precede dysplasia and is more widespread
throughout the mucosa of UC patients[15].
CRC risk factors
Several factors have been identified which either increase
or decrease CRC risk in the setting of IBD (Table 1). With
respect to increasing CRC risk, the most important factor,
reproducibly found across many studies, is the duration
of colitis. CRC is rarely encountered before 7 years of
colitis. The pooled estimate of cumulative CRC incidence
in UC in Eadens meta-analysis was 2% at 10 years, 8%
at 20 years, and 18% after 30 years of disease[2]. This may
overestimate the risk since many studies in the meta-
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January 21, 2008 Volume 14 Number 3
Table 1 Factors associated with CRC risk
Factors that increase CRC risk
Longer duration of colitis
Greater extent of colonic involvement
Family history of colorectal cancer
Primary sclerosing cholangitis
Young age of IBD onset (some studies)
Backwash ileitis (possibly)
Severity of histologic inflammation
History of dysplasia
Factors that decrease CRC risk
Prophylactic total proctocolectomy
Regular doctor visits
Surveillance colonoscopy
Chemoprevention
analysis were from the pre-surveillance era. Thus, a recent
study by Rutter et al showed lower cumulative incidence
of CRC in patients with UC even at the referral-based St.
Marks Hospital in London: 2.5% after 20 years of disease,
7.6% after 30 years, and 10.8% after 40 years of follow-
up[16].
Extent of colitis is an independent risk factor for the
development of CRC. The more colonic surface that is
involved with colitis, the greater the CRC risk. However,
different criteria exist regarding classification of the extent
of colitis. Most early reports of surveillance programs
used barium enema results at diagnosis as the standard
for defining disease extent. A population-based study of
over 3000 UC patients in Sweden examined by barium
enema demonstrated that patients with proctitis had a
standardized incidence ratio (SIR) of 1.7 [95% confidence
inter val (CI) 0.8-3.2] compared with age-matched
population controls without UC, whereas those with left-
sided colitis had a SIR 2.8 (95% CI 1.6-4.4), and those
with pancolitis had SIR 14.8 (95% CI 11.4 to 18.9) [17].
Endoscopic and histologic evidence of inflammation are
valid alternative criteria particularly in high risk patients.
Very few studies have correlated CRC risk with histologic
extent of disease, even though microscopic evidence
of colitis is arguably a better indicator of disease extent
than either endoscopic or radiographic changes. Mathy
et al[18] reviewed 30 colectomy specimens and showed that
dysplasia and CRC can arise in areas of microscopic colitis
that are proximal to areas of gross colitis, suggesting that
indeed histologic changes, even without colonoscopic
alterations, might better define disease extent for the
purposes of cancer risk. Backwash ileitis, defined as
pancolitis with superficial involvement of the terminal
ileum, has been suggested as an additional increased risk
of CRC[19], but this requires additional confirmation.
IBD patients with a family history of CRC have at least
a two-fold higher risk of CRC[20-22]. Both UC and Crohns
disease patients with primary sclerosing cholangitis (PSC)
are at particularly high risk for developing colorectal
neoplasia [23]. In a population-based Swedish study, the
cumulative incidence of CRC in UC patients with PSC
was 33% at 20 years[24]. By comparing patients with UC
with and without PSC, Shetty et al[25] reported an adjusted
relative risk (RR) for dysplasia or cancer of 3.15 (95%
CI, 1.37 to 7.27) in patients with PSC. Current practice
 Xie J et al. Cancer in IBD
guidelines recommend all patients with PSC not previously
known to have IBD should undergo a colonoscopy to
determine their status. For those patients with IBD,
screening and subsequent surveillance should begin at
the diagnosis of PSC, and if the patient progresses to
the point at which liver transplantation is necessary,
prophylactic colectomy should be considered. Young age
at onset of colitis has been reported to be an independent
risk factor for CRC in some[2,17,26], but not all studies[27,28].
There is insufficient evidence to support starting screening
and sur veillance before 8 years of disease in these
patients. The severity of colitis has not been considered
an independent risk factor for CRC when activity of
disease is defined according to the frequency of clinical
exacerbations[22]. However, a case-control study by Rutter
et al showed that increased severity of inflammation, both
endoscopically and histologically, correlates with increased
frequency of dysplasia[29]. It is important to realize that the
patient with quiescent IBD is also at increased CRC risk.
With regard to reducing CRC risk, there are two main
choices: removing the colon versus conducting a lifelong
program of surveillance (Table 1). Although prophylactic
total proctocolectomy after 7-10 years of colitis would
prevent most cancers, it would result in many colectomies
that were not necessary and a substantially altered quality
of life for patients. Thus cancer prevention in this
patient population has focused on periodic surveillance
colonoscopies. Surveillance should be viewed as a program
that includes regular visits to the doctor, the use of
medications to control inflammation (some of which may
have chemopreventive effects, see below), and regular
colonoscopies. The goal of surveillance colonoscopy is to
detect neoplastic lesions before they become biologically
dangerous. Thus, the detection and interpretation of
dysplasia is crucial to successful surveillance.
DIAGNOSING DYSPLASIA
Macroscopic classification of dysplasia
By definition, dysplasia is unequivocal neoplasia. Despite
considerable heterogeneity in appearance[30], dysplasia in
IBD is often classified macroscopically as raised or flat,
depending on whether it corresponds to an endoscopically
visible lesion. Raised lesions, conventionally referred
to by the term DALM (dysplasia associated lesion or
mass)[13], can appear as polyps, bumps, plaques and velvety
patches[31,32]. Such lesions can blend easily with the gross
inflammatory abnormalities commonly encountered in
colons with IBD, making their endoscopic detection
difficult even for experienced practitioners.
Unlike sporadic cancers arising from polypoid lesions,
IBD-associated cancers can arise from flat dysplastic
lesions. Flat dysplasia is detected microscopically in
random biopsies from unremarkable mucosa. Its detection
therefore depends on adequate sampling of the mucosa by
the endoscopist, or more recently, by chromoendoscopy
methods which highlight suspicious lesions and permit
targeted biopsies (see below). If random biopsies are
performed without dye spray enhancement, it has been
estimated that to exclude dysplasia with a 90% certainty,
33 biopsy specimens are required, and to increase the
381
accuracy to 95%, nearly twice the number of biopsy
specimens are required[33]. Current surveillance strategies
recommend annual colonoscopy with multiple biopsy
specimens (4 circumferential) taken from every 10 cm of
diseased colon, with additional biopsy specimens at sites
of strictures or raised lesions[34]. However, questionnaire
surveys have suggested that the number of biopsies taken
by endoscopists in routine practice often falls short of
recommended guidelines[35,36].
The significance of dysplasia in endoscopically
visible lesions came from studies that reported high rates
of cancer when patients with such lesions underwent
colectomy[31,32]. Blackstone et al reported cancers in 7 of
12 DALM-bearing colons, including 5 with only mild
or moderate dysplasia in the preoperative biopsies[31]. A
subsequent compilation of published results from ten
surveillance programs reported cancers in 17 of 40 (43%)
colectomies performed because of a DALM [37]. It was
concluded that DALM is an indication for colectomy
irrespective of the grade of dysplasia in preoperative
biopsies. While not fully appreciated at the time, the
original studies of DALMs dealt exclusively with lesions
that could not be removed endoscopically for microscopic
examination. Thus, the significance of such lesions as an
indication for surgery is similar to that of endoscopically
non-resectable sporadic adenomatous polyps, which
frequently harbor invasive cancer at the polyp base despite
the presence of low-grade dysplasia in their more biopsy-
accessible upper portions.
More recently, we have come to realize that not all
types of polypoid dysplasia in patients with IBD carry
the same significance. Some polyps may be adenomatous
polyps unrelated to colitis and can be managed by
endoscopic polypectomy like polyps in the general
population [38-40] . One example is the dysplastic polyp
encountered in a bowel segment that is entirely free of
disease (e.g., in the proximal colon of a patient with left-
sided ulcerative colitis). In such cases, one would take the
precaution to biopsy the mucosa surrounding the polyp
to assure the absence of microscopic disease. Similarly, a
dysplastic polyp with a well-defined stalk can be regarded
as a sporadic adenoma, even when encountered in a colitic
region, if the mucosa lining its stalk is non-dysplastic.
Conservative management is also reasonable for
dysplastic polyps that are adenoma-like [41,42]. These
polyps are endoscopically indistinguishable from sporadic
sessile adenomatous polyps, i.e., discrete and ovoid or
round, are completely resectable by the endoscope, and are
not surrounded by flat dysplasia. Such lesions have long
posed a dilemma for endoscopists who were familiar with
the DALM concept but reluctant to advocate colectomy
for what appeared to be innocuous lesions and possibly
nothing more than fortuitous adenomas. Histology has
not provided a reliable means of making this distinction
in individual cases[43], since the histological features of
dysplasia in the setting of IBD and in true adenomas
can be virtually identical. A 1999 study from The Mount
Sinai Hospital in New York reported that conservative
management of a cohort of 48 UC patients with a total
of 70 such polyps, including 3 with high-grade dysplasia,
resulted in no adverse outcomes during a mean follow-up
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 382 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol
period of 4.1 years[41]. Similar conclusions were reached in
a concurrent study from Brigham and Womens Hospital[42]
that was confirmed upon longer follow-up [44] . As a
result, the burden of deciding whether a polyp qualifies
as adenoma-like rests with the endoscopist. Molecular
markers may ultimately afford a more objective means of
making these distinctions[45,46], but to date, these analyses
are not applicable to routine clinical practice.
Microscopic classification of dysplasia
Gastrointestinal dysplasia is defined microscopically as
replacement of the native intestinal epithelium by an
unequivocally neoplastic, but noninvasive, epithelium[47].
It is synonymous with the term intraepithelial neoplasia
used in other organ systems. A standardized classification
system of dysplasia in IBD was established and divided
dysplasia into five categories: negative for dysplasia,
indefinite for dysplasia, low-grade dysplasia (LGD), high-
grade dysplasia (HGD) or invasive cancer[47]. A further
subdivision of the indefinite category includes probably
negative, probably positive, unknown, however many
pathologists regard this as optional.
The cellular abnormalities that define dysplasia in
IBD are analogous to those characterizing neoplastic
tissue in general, namely nuclear abnormalities reflecting
inappropriate cellular proliferation and cytoplasmic
abnor malities reflecting clonality and aberrant
differentiation. The distinction between low- and high-
grade dysplasia depends upon the distribution of nuclei
within the cells, low-grade dysplasia being characterized by
nuclei that remain confined to the basal half of the cells
and high-grade by nuclei that are stratified haphazardly
between the basal and apical halves[47]. Not surprisingly,
pathologists are frequently confronted with biopsies
that lie in a gray zone between the two categories, and
some degree of subjectivity is therefore unavoidable.
The diagnostic category indefinite for dysplasia is an
acknowledgement of the difficulty pathologists face in
discriminating between dysplasia and reactive epithelial
changes, although experienced pathologists are usually able
to discriminate between the two.
There is inconsistency among pathologists in the
diagnosis of dysplasia on biopsy. In one study[48], there was
only 60% agreement for a diagnosis of LGD. Similarly Lim
et al[49] found that the kappa coefficient for interobserver
agreement between ten pairings of five specialist
gastrointestinal (GI) pathologists ranged from 0.06 to
0.39. Other studies comparing diagnoses of dysplasia
among different pathologists, both prospectively and
retrospectively, have concluded that levels of interobserver
agreement are fair at best even among specialists in
gastrointestinal pathology[50-54]. The best agreement levels
tend to occur at the two extremes of negative and high-
grade dysplasia and the poorest levels in the two gray
zones between low-grade and high-grade dysplasia and
on either side of indefinite for dysplasia. From a practical
standpoint, it has been recommended that diagnoses
carrying serious management implications be reviewed by
at least one additional pathologist with expertise in this
area[55].
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January 21, 2008 Volume 14 Number 3
BIOLOGY OF DYSPLASIA
Natural history of dysplasia
The natural history of dysplasia is a key factor contributing
to the outcome and success of surveillance. The model
shown in Figure 1 suggests that colitic mucosa progresses
in a systematic fashion: no dysplasia, indefinite dysplasia,
LGD, HGD, and finally invasive cancer. Although this is
a useful paradigm that facilitates the study of cancer risk
markers in IBD, it remains unclear whether dysplasia of
one grade may progress (or regress) to another grade.
For example, patients undergoing regular colonoscopic
surveillance have developed CRC without any prior
dysplasia, and it is not necessary for LGD to progress to
HGD before cancer arises in the colon[30,56]. This highlights
the need to develop markers that are complementary to
dysplasia for predicting CRC risk in IBD patients-a subject
of ongoing investigation.
In the meantime, we currently rely upon the histological
identification of dysplasia to make management decisions.
Refinements in interpreting dysplasia based on the 1983
standardized histological criteria[47] have enabled a more
accurate prediction of which patients are more likely
to progress to advanced neoplasia by excluding those
whose biopsies only show reactive changes secondary
to inflammation. This was amply illustrated by the St.
Marks group who found that the 5-year cumulative rate of
progression from LGD to HGD or cancer rose from 16%
to 54% once biopsies were more precisely reclassified[53,57].
Dysplasia (of any grade) is associated with a risk
of concurrent CRC in IBD. An early study reported
12 cases, described as unresectable single polypoid masses,
collections of polyps, or plaque-like lesions, 7 were
found to have adenocarcinoma upon colectomies despite
multiple biopsies that had not detected it[31]. In a review
of ten prospective surveillance trials, 43% of patients who
underwent colectomy because of DALM had coexistent
CRC, 42% (10 of 24) patients with HGD, and 16%
(3 of 19) patients with LGD who underwent immediate
colectomy had synchronous CRC[37]. Ullman and colleagues
at The New York Mount Sinai Hospital performed a
retrospective cohort analysis of 46 patients with UC who
had flat LGD but did not undergo immediate colectomy.
They found that 27% (3 of 11) patients who underwent
colectomy within 6 months of the initial detection of flat
LGD had a surprise finding of cancer or HGD[56]. More
recently, Rutter et al from the St. Marks Hospital reported
20% of patients with LGD who proceeded to colectomy
had concurrent adenocarcinoma and 39.1% who had
follow-up of the LGD progressed to subsequent HGD or
CRC[16].
Assuming that early colectomy is not performed,
what is the subsequent rate of progression? In the case
of patients with HGD, 32% were found to have CRC
after some follow-up period[37]. For those with LGD, the
probability of eventually progressing to HGD or CRC
was 16%-29%[37]. Data from St. Marks Hospital indicate
that the 5-year cumulative probability of progressing
from LGD to HGD or cancer is 54%[53]. Strikingly similar
results were obtained from The Mount Sinai Hospital,
with a 5-year progression rate of 53% among 46 patients
 Xie J et al. Cancer in IBD
with initial flat LGD [56]. A recent follow-up analysis
from the St. Marks group indicates slightly lower, but
still substantial rates of progression[16]. Likewise, a series
of 18 patients with LGD followed at the Mayo Clinic
demonstrated a 33% 5-year progression rate[58]. Despite
these rather similar results from three different patient
populations, some authors have reported a substantially
lower rate of progression. Befrits et al followed 60 patients
with flat LGD from the Karolinska Institute in Sweden
and found that none developed cancer and only 2 cases
of progression to HGD in DALMs over a mean follow-
up period of 10 years[59]. In the series by Lim et al from
Leeds in the U.K., they reported that only 3/29 (10%)
patients with LGD progressed to HGD or cancer after 10
years[49]. It is worth noting that in the latter two studies,
the designation of LGD included specimens that were
interpreted prior to the 1983 consensus guidelines, so they
might have included cases with indefinite dysplasia.
Because of uncertainty of flat LGD[56,60], these studies
have failed to achieve consensus on proper management
of flat LGD. Hence, competing options should be
discussed with each patient. A patient confirmed to
have multifocal flat LGD (2 or more biopsies with LGD
from a single screening or surveillance examination) or
repetitive flat LGD (2 or more examinations with at least
a single focus of LGD), should be strongly encouraged to
undergo prophylactic total proctocolectomy. Furthermore,
even for patients with confirmed unifocal LGD (only 1
biopsy positive for LGD in a screening or surveillance
examination) should also be offered the option of
undergoing prophylactic proctocolectomy, since evidence
indicates that a 5-year rate of progression to HGD or
CRC in this patient group seems to be similar to that of
multifocal LGD[56].
THE MANAGEMENT OF DYSPLASIA
Once a decision is made to place a patient under
surveillance, it is recommended that the patient formally
agree to enter such a program and is willing to comply.
Patients must be made to understand the limitations of
surveillance and accept the concept that despite their own
cooperation, dysplasia and cancer can still arise even in the
hands of skilled endoscopists and pathologists[53].
The best proof that sur veillance colonoscopy
effectively reduces CRC mortality would be a prospective,
randomized, controlled trial in which patients with
longstanding IBD would underg o colonoscopic
surveillance whereas controls matched for a similar risk
profile would not. However, due to ethical, financial and
practical limitations, this type of study will likely never
come to pass. We must therefore rely on retrospective
studies for insights as to the efficacy of surveillance
colonoscopy. In a retrospective study by Choi et al, patients
with chronic UC who developed cancer were divided into
those who had surveillance colonoscopy and those who
did not. Patients undergoing surveillance colonoscopy were
found to have less advanced Dukes stage CRC than those
who did not and correspondingly had an improved 5-year
survival rate (77.2% vs 36.3%, P = 0.026)[61]. However, the
best evidence that colonoscopy reduces mortality from
383
CRC in UC comes from case-control studies. In one such
study, Karlen and colleagues identified 2 of 40 patients
with UC and 18 of 102 controls who had undergone at
least one surveillance colonoscopy who died as a result
of CRC (RR = 0.29), CRC mortality was reduced by
as much as 78%, although this did not reach statistical
significance[62]. Another study found a similar degree of
protection[22]. In these studies, a protective effect was found
for individuals who had even one or two surveillance
exams. There is also good evidence from prospective,
albeit uncontrolled, studies of surveillance colonoscopy
that in general, patients who comply with surveillance have
cancers detected at earlier stages compared to those who
do not comply[53,63]. Of course, cancers will still arise even
within a surveillance program, but in balance, the practice
of surveillance is beneficial[64].
Although the gastroenterology community has put
its faith in surveillance colonoscopy to prevent CRC in
IBD patients, surveillance has its limitations. Previous
studies have shown low rates of observer agreement for
the histopathologic interpretation of biopsy specimens
between general pathologists and GI pathologists, or
even among expert GI pathologists [47,48]. Endoscopists
fail to take a sufficient number of biopsies to exclude the
presence of dysplasia or cancer[33]. Unlike the dysplastic
sporadic adenoma which typically assumes a discrete,
polypoid shape surrounded by normal mucosa, dysplasia
in the colitic colon can be flat or polypoid and is often
difficult to discern. This may be particularly troublesome
in a colon that is replete with inflammatory pseudopolyps.
Furthermore, there is poor understanding of dysplasia
amongst trained gastroenterologists. A survey of practicing
gastroenterologists and senior GI fellows in the U.S.
found that only 19% of respondents correctly identified
dysplasia as neoplastic change[35]. Patient drop-out or non-
compliance with surveillance contributes importantly to
CRC mortality in IBD[49,53] and this must be considered
when embarking upon, or continuing, a course of
surveillance in individual patients.
RECOMMENDED SURVEILLANCE
STRATEGY
Despite the limitations of surveillance colonoscopy,
dysplasia remains the best marker for managing cancer risk
in IBD. After approximately 7-8 years of colitis, patients
should undergo an initial surveillance colonoscopy to
determine the extent of colitis and check for neoplasia[55].
The entire colon should be examined, with approximately
4 biopsies taken every 10 cm. Some experts suggest
taking more biopsies in the distal rectosigmoid (e.g.,
approximately every 5 cm) since the distribution of
neoplasia in UC still shows a distal predominance. Biopsies
should be taken from flat mucosa, but if any raised or
suspicious lesions are encountered, these should be
removed if possible and processed in separate specimen
containers (with additional biopsies taken near the base of
the polyp). If a patient is experiencing moderate-severe
colitis symptoms, one option is to control the inflammation
medically prior to performing the examination in order to
minimize difficulties with the histological interpretation of
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 384 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol
High-grade Low-grade
dysplasia dysplasia
Flat Polypoid Flat Probably
positive
or
Repeat
colonoscope
Colectomy within 3-6 mo
Discrete, adenoma-like Repeat colonoscope
polyp that is completely within 6 mo:
removed & repeated dysplasia
no flat dysplasia elsewhere? confirmed?
No Yes
Yes No
dysplasia. However, one should not defer the colonoscopy
too long, since many expert pathologists now feel that
they can readily interpret dysplasia even in the presence of
active inflammation.
Figure 2 depicts a recommended surveillance strategy.
If no dysplasia is detected, the examination should be
repeated in 1-2 years. This interval derives in part from
studies reporting that interval cancers can develop within
2 years after a surveillance examination[53]. If indefinite
dysplasia is reported, the nature of the uncertainty should
be discussed with the pathologist. If the suspicion of
dysplasia is high (i.e., probably positive), repeat biopsy
within 3-6 mo or less may be indicated; if low, the interval
can be lengthened to every 6-12 mo. If LGD is detected in
a discrete polyp that can be readily resected endoscopically
and there is no flat dysplasia immediately adjacent to
the polyp or elsewhere in the colon, surveillance can
be continued, although the frequency of examinations
can be temporarily reduced to every 3-6 mo, particularly
to re-evaluate the area of polypectomy. Tattoo of the
polypectomy site is advised to permit relocalization of
the area on subsequent exams. If LGD is detected in flat
mucosa (whether unifocal or multifocal), and is confirmed
by a second expert GI pathologist, colectomy should
be strongly considered. If the patient refuses, repeat
surveillance exams should be undertaken within 3-6 mo
or less. However, the patient should be advised that a
negative subsequent examination is no assurance of safety,
and that temporizing until there is histological progression
to HGD or cancer as the indication for colectomy is
risky. A patient in whom flat HGD or adenocarcinoma is
found and confirmed by two expert pathologists should
undergo colectomy unless serious co-morbidities dictate
otherwise. If HGD is diagnosed in an adenoma-like
polyp but it is completely removed without evidence of flat
dysplasia in the adjacent mucosa or elsewhere in the colon,
continued surveillance can be entertained. As with any set
of recommendations, decisions should be individualized
according to the situation of the patient. Hopefully,
strategies for surveillance will become more refined as more
knowledge of the natural history of dysplasia is obtained.
www.wjgnet.com
January 21, 2008 Volume 14 Number 3
Indefinite No Figure 2 Suggested management scheme
dysplasia dysplasia for dysplasia. Modified from Ref 71. With
permission.
Probably
negative
Repeat
colonoscope
within 6-12 mo
Repeat
colonoscope
in 1-2 year
Patients who have only had small intestinal Crohns
disease without colonic involvement are not considered
to be at high risk for CRC. For patients with Crohns
colitis, much less is known. To date, only one practice-
based retrospective surveillance study has been reported
in patients with Crohns colitis[65]. Of 259 patients with
Crohns colitis affecting at least one-third of the colon
for at least 8 years, 16% were found to have dysplasia or
cancer over a 16 year period in which 663 examinations
were performed, and there were no cancer deaths. While
we await additional data on the subject, it seems wise to
follow a UC-based surveillance strategy for patients with
at least 8 years of substantial Crohns colitis. An important
question that remains to be clarified is whether patients
with dysplasia or cancer in the setting of segmental Crohns
colitis can undergo segmental resection of the involved
area or should proceed to a more extensive UC-like
surgical approach. Another dilemma that is encountered
with Crohns colitis is the management of strictures. This
occurs more so than with UC. Finding a stricture in a
colon of a patient with UC usually means an underlying
malignancy, especially if the stricture is causing symptoms,
and is located in the proximal colon[66]. However, since most
strictures in Crohns colitis are benign, the patient can often
be managed conservatively. Surveillance of such patients
often requires using a narrower colonoscope or sometimes
dilating a stricture to visualize the proximal mucosa[65].
Consideration should be given to adding brush cytology
of strictures to regular forceps biopsies, and performing a
barium enema to evaluate for colonic wall irregularity.
New endoscopic techniques and molecular screening
approaches
Recent publications on chromoendoscopy have demon-
strated a greater yield for dye-spray targeted biopsies
compared with numerous non-targeted biopsies and thus
enhance the endoscopic detection of dysplastic lesions in
colitic colons. In a randomized trial by Kiesslich et al[67],
intraepithelial neoplasia was more than three times as likely
to be detected using chromoendoscopy compared with
surveillance using nontargeted biopsies (32/84 compared
 Xie J et al. Cancer in IBD
with 10/81; P = 0.003). Rutter et al detected no dysplasia in
2904 non-targeted biopsies in 100 patients, but in targeted
biopsies, nine dysplastic lesions were detected, seven of
which were visible only with dye spraying by using indigo
carmine instead of methylene blue[68]. A recent report
by Ochsenkuhn et al from Munich, Germany showed a
low frequency of colorectal dysplasia in patients with
long-standing IBD by fluorescence colonoscopy with
5-aminolevulinic acid[69].
Other approaches worth mentioning are to examine
the biopsy tissue of patients with IBD for molecular
alterations. The best tested of these are aneuploidy,
mutations in p53 and ras, and glycosylation abnormalities,
particularly increased expression of sialyl Tn antigen (sialyl
2,6 N-acetylgalactosamine)[70]. Because the DNA shed into
stool should theoretically provide a more comprehensive
sampling of abnormal cells than random pinch biopsies,
stool DNA testing could potentially contribute to the
management of patients with long-standing IBD who are
at risk for developing CRC.
Chemoprevention
Despite the relative protection afforded by surveillance
colonoscopies in IBD, there are still patients who develop
CRC despite seemingly optimal surveillance. This raises the
issue of whether chemoprevention in the form of either
medications or dietary supplements might help reduce the
risk of CRC in IBD[71].
Aspirin and other NSAIDs markedly reduce the
incidence of, and mortality from, sporadic CRC. Since
many patients with IBD take NSAIDs in the form of
5-aminosalicylates (5-ASA), investigators have asked whether
5-ASA compounds might also be protective. Although no
study to date has been performed in a prospective manner
specifically to address this question, the available data
suggest that this may be so[72]. If 5-ASA compounds prevent
colonic neoplasia by suppressing inflammation, it follows
that other anti-inflammatory medications used in IBD
patients should also be protective against CRC. Although
one study reported that the use of systemic steroids,
and even topical steroids resulted in a significant CRC
risk reduction[22], and others confirm this observation[73],
steroids cannot be used long-term for chemoprevention.
There appears to be no chemopreventive activity of
6-mercaptopurine or azathioprine[74].
In the setting of sporadic CRC, low folate intake has
been associated with an increased risk for developing
colorectal adenomas and carcinomas[75,76]. Patients with
chronic IBD are predisposed towards folate deficiency
because of inadequate nutritional intake, excessive intestinal
losses with active disease, and reduced intestinal absorption
from competitive inhibition from sulfasalazine use. Results
of two studies suggest a trend towards protection against
CRC in folate users, although neither study demonstrated
statistical significance[77,78]. Nonetheless, since it is rather
safe and inexpensive, folate supplementation should
be considered for CRC risk reduction in patients with
longstanding IBD.
In animal models of colon carcinogenesis, ursodiol
inhibits carcinogenesis-an effect that may be due to
the ursodiol reducing the colonic concentration of the
385
secondary bile acid deoxycholic acid. Ursodiol also has
anti-oxidant activity. A study of UC patients with PSC
demonstrated that ursodiol use was strongly associated
with decreased prevalence of colonic dysplasia[79]. This
protective effect remained after adjusting for duration of
colitis, age at onset of colitis, and sulfasalazine use. In a
follow-up to the randomized, placebo-controlled trial by
Pardi et al at the Mayo Clinic, 52 patients with chronic PSC
and chronic UC (mean 13 years) were followed for a total
of 335 person-years. Ursodiol use was associated with a
significant protection against the development of dysplasia
and cancer (RR = 0.26, P = 0.034)[80]. At the present time,
however, we do not know whether ursodiol can prevent
neoplastic progression in UC patients without PSC.
Recently, there has been interest in the role statins may
play as chemopreventive agents in a variety of cancers. In
a population-based case-control study of patients who had
diagnosis of CRC in northern Israel between 1998-2004,
statin therapy was associated with a modest reduction in
CRC in the non-IBD population, but a substantial 94%
risk reduction in patients with IBD was observed in a
subset analysis of a small number of patients[81]. Further
studies will need to verify this benefit.
Although a single retrospective cohort study suggests
that therapy with 6-mercaptopurine is not chemopreventive
(or carcinogenic), there remain insufficient data regarding
the chemopreventive role of immunomodulators in order to
make recommendations and likewise, whether patients who
require immunomodulator therapy should continue their
5-ASA therapies[74].
Small bowel cancer in IBD
Most cancers of the small bowel in Crohns disease are
adenocarcinoma, usually in the terminal ileum or jejunum.
The most common clinical presentation of small bowel
cancer is intestinal obstruction [82] . Other important
symptoms include diarrhea, weight loss, and abdominal
fistulae. These symptoms are also found in Crohns
disease. Risk factors for developing carcinoma in small
bowel segments of involved mucosa in patients with
Crohns disease are poorly defined, although case reports
document them in strictured mucosa and fistulae [83-85].
Surgery should be considered if the fistulae or stricture
cannot be adequately examined, or symptoms substantially
worsen. There is some suggestion that 5-ASA compounds
might lower the risk of small intestinal adenocarcinoma[86].
A number of studies have demonstrated an increased
risk of developing adenocarcinoma of the small intestine
with small intestinal Crohns disease. Although the
absolute number of cases of small bowel adenocarcinoma
is low, because of the rarity of this cancer in the general
population, the risk is approximately 10-12-fold greater
than the general population[4,86]. In the Uppsala study[87], the
investigators reported only one observed case compared
with 0.3 expected cases, but the confidence interval was
wide. In the Copenhagen study[88], two cases were observed
vs 0.04 expected cases, a 50-fold increased occurrence.
In the Tel Aviv study[89], none of the patients developed
small cancer. The material was probably far too small to
expect any small bowel cancer cases. In Oxford, a 10-fold
increased relative risk was observed for cancer of the small
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 386 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol
intestine[90]. A population-based Swedish study revealed
a significantly increased number of cancer of the small
intestine (standardized morbidity ratio, 15.64; 95% CI,
4.26-40.06), however, the occurrence of colorectal cancer
was not increased[91]. Another population-based Canadian
study encompassing the years 1984-1997 demonstrated an
increased incidence rate ratio of carcinoma of the small
intestine (17.4; 95% CI, 4.16-72.9)[4].
Pa ti en ts wi th U C w h o h ave u n d e r g o n e t o t a l
proctocolectomy with ileal pouch anal-anastomosis (IPAA)
have a very small risk of dysplasia arising within the ileal
mucosa of the pouch itself. The risk is thought to be
higher in patients with chronic pouchitis and associated
severe villous atrophy[92], but this has not been shown in all
series[93]. Indeed, a study of 160 patients who underwent
biopsy a total of 222 times with an average surveillance
time of 8.4 years after surgery showed that in 1800 pouch-
years of surveillance, only one patient had focal LGD
of the pouch[94]. The risk of neoplasia is greater in the
anal transitional mucosa between the pouch and the anal
canal, particularly if a cuff of rectal mucosa has been left,
and if the indication for the IPAA was rectal dysplasia
or cancer[95]. While there are currently no guidelines for
endoscopic surveillance after an IPAA procedure, in
those patients who have chronic pouchitis and severe
villous atrophy or whose original indication for IPAA was
dysplasia or cancer, a program of periodic endoscopy with
biopsies, paying particular attention to any anal transition
zone, is reasonable.
Other cancers in patients with IBD
Squamous cell carcinoma of the anus has been reported in
patients with longstanding, complicated perianal Crohns
disease[85]. Worsening perianal symptoms in such patients
should warrant heightened vigilance for this tumor which
often requires examination under anesthesia for adequate
tissue diagnosis.
An increased risk for hepatobiliary cancers in patients
with UC has been found in several[4,96-98] but not all[87]
studies. For many of these patients, primary sclerosing
cholangitis was the predisposing factor.
The risk of hematopoietic cancer in patients with IBD
has been a growing concern. Early case series from The
Cleveland Clinic[96] and The Mount Sinai Hospital[99], as
well as other centers[100] reported an increase in leukemia
in patients with UC. A recent large cohort study from
Sweden[101], which included nearly 50000 IBD patients
concluded this population has a marginally increased risk
of hematopoietic cancer, and in UC, lymphoma occurred
as expected (SIR 1.0) but myeloid leukemia occurred
significantly more often than expected (SIR 1.8). In Crohns
disease, there was a borderline significant increased
lymphoma risk (SIR 1.3), essentially confined to the first
years of follow up. However, population-based studies
from Denmark [97], Sweden [87] and Canada [4] have failed
to substantiate any increased risk of leukemia. Likewise,
although an increased number of lymphomas have been
reported in some case series [99,102], other series [96] and
several population-based studies[87,91,97,98] do not support
the notion that patients with UC or Crohns disease are
at increased risk of lymphoma. However, a population-
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January 21, 2008 Volume 14 Number 3
based study from Canada reported an increased rate of
lymphoma among male patients with Crohns disease[4].
The risk of lymphoma or leukemia in IBD has
raised concerns regarding the lymphogenic potential of
immunomodulatory therapy. Following the introduction
of tumor necrosis factor inhibitors in the treatment of
Crohns disease, subsequent reports indicated an excess
of malignant lymphoma among treated patients[103,104] and
raised fears of an iatrogenic lymphoma risk. However,
these reports have also highlighted the lack of robust data
on the expected occurrence of malignant lymphomas in
TNF nave (but otherwise treated) patients with IBD[105-107].
Studies examining the risk of lymphoma associated
with azathioprine (AZA) and 6-mercaptopurine (6-MP)
have yielded variable results. Heterogeneity in the type,
dose, and duration of immunomodulatory therapy may
be responsible for this discrepancy. A few studies with
suboptimal dosing failed to demonstrate an increased risk
of lymphoma[4,108-112]. In contrast to these reports, other
studies have demonstrated an increased risk of lymphoma
after purine analog therapy [113-115]. In one such study,
Kandiel et al reported a 4-fold-higher risk of lymphoma
inpatients treated with AZA or 6-MP compared with
the general population[114]. Another recent study showed
a statistically significant increase in the development of
malignancies among IBD patients treated with 6-MP who
developed sustained leucopenia[115].
FUTURE DIRECTIONS
The future looks promising with respect to new
developments in the management of cancer risk in
IBD. Chromoendoscopy is likely to be used more for
management, but whether the predictable increase in
the yield of dysplasia will alter the overall natural history
remains to be studied. In the modern era of molecular
diagnostics, tissue and even stool samples of patients
with IBD can be investigated for molecular alterations.
For example, University of Washington investigators
have demonstrated that because there is often widespread
genomic instability throughout the colon of IBD
patients, it may be possible to analyze rectal biopsies by
DNA fingerprinting or fluorescence in situ hybridization
methods[116] to identify patients at particularly high risk.
The advent of technology to extract human DNA from
stool and look for specific DNA mutations associated with
sporadic colon carcinogenesis[117,118] implies that a similar
approach may also be worthwhile in IBD patients. It is
anticipated that refinements in our knowledge of cancer
biology, clinical practice, and molecular discovery will
bring a new level of sophistication to the management of
patients with longstanding IBD and lower the incidence of
CRC in this high-risk population.
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